It has been generally established that hyperlipidemia (high levels of lipids in blood plasma) is associated with several health related disfunctions such as atherosclerosis, diabetes, and obesity. Blood cholesterol levels have been particularly implicated in the incidence of atherosclerosis. More particularly, a high risk of cardiovascular disease has been shown to correlate with the ratio of low density lipoprotein (LDL) cholesterol to high density lipoprotein (HDL) cholesterol. Agents which can reduce the ratio of LDL/HDL have been shown to effectively lower the incidence of cardiovascular disease associated with atherosclerosis. While it is preferable to reduce the LDL/HDL ratio by reducing the level of LDL in blood plasma, reduction of the LDL/HDL ratio without significantly reducing the level of LDL has also been shown to correlate with lower risk of cardiovascular disease.
More recently, it has been shown that there is a relationship between blood levels of the enzyme pseudocholinesterase and hyperlipidemia. The possible treatment of hyperlipidemia by inhibition of blood plasma pseudocholinesterase is suggested by Kutty, K. M., R. Redheendran & D. Murphy, "Serum Cholinesterase: Function in Lipoprotein Metabolism", Experientia, Vol. 33 (1977), pp. 420-422. A study published in Kutty, K. M., R. Jain, S.-N. Huang & K. Kean, "Serum Pseudocholinesterase: High Density Lipoprotein Cholesterol Ratio as an Index of Risk for Cardiovascular Disease", Clinica Chimica Acta, Vol. 115 (1981), pp. 55-61, indicates that there is a significant increase in the ratio of plasma pseudocholinesterase/HDL cholesterol in subjects classified as high risk for cardiovascular disease on the basis of the ratio of total cholesterol/HDL cholesterol. The results of this study of 290 subjects suggest that plasma pseudocholinesterase has a parallel relationship with LDL and a reciprocal relationship with HDL. Further studies reported in Jain, R., K. M. Kutty, S.-N. Huang & K. Kean, "Pseudocholinesterase/High-Density Liproprotein Cholesterol Ratio in Serum of Normal Persons and of Hyperlipoproteinemics", Clinical Chemistry, Vol. 29 (1983), pp. 1031-1033, show that the ratio of plasma pseudocholinesterase/HDL cholesterol is particularly high in subjects with certain types of hyperlipidemia. Similar results showing a correlation between high blood levels of pseudocholinesterase and hyperlipidemia are disclosed in Cucuianu, M., T. A. Popescu & S. Jaragus, "Pseudocholinesterase in Obese and Hyperlipemic Subjects", Clinica Chimica Acta, Vol. 22 (1968), pp. 151-155; Cucuianu, M., T. A. Popescu, A. Opincaru & S. Haragus, "Serum Pseudocholinesterase and Ceruloplasmin in Various Types of Hyperlipoproteinemia", Clinica Chimica Acta, Vol. 59 (1975), pp. 19-27; Cucuianu, M., A. Opincaru & D. Tapalaga, "Similar Behavior of Lecithin:Cholesterol Acyltransferase and Pseudocholinesterase in Liver Disease and Hyperlipoproteinemia", Clinica Chimica Acta, Vol. 85 (1978), pp. 73-79; and Cucuianu, M. P., A. Cristea, S. Roman & I. Missits, "Increased Plasma Antithrombin III Level in Hyperlipidemic Subjects", Clinica Chimica Acta, Vol. 110 (1981), pp. 147-155. A study reported in Ando, M., S. Hirosaki, K. Tamura & T. Taya, "Multiple Regression Analysis of the Cholinesterase Activity with Certain Physiochemical Factors", Environmental Research, Vol. 33 (1984), pp. 96-105, shows a significant positive correlation between blood plasma pseudocholinesterase levels and serum total cholesterol content.
Animal studies have shown that agents which inhibit cholinesterase activity will significantly decrease plasma LDL and/or significantly increase plasma HDL levels as reported in Kutty, Redheendran & Murphy, and in Kutty, K. M., J. D. Jacob, C. J. Hutton, P. J. Davis & S. C. Peterson, "Serum Beta-Lipoproteins: Studies of a Patient and in Guinea Pigs After the Ingestion of Organophosphorus Compounds", Clinical Biochemistry, Vol. 8 (1975), pp. 379-383. In Kutty, Jacob, Hutton, Davis & Peterson, it is reported that in a patient accidentally poisoned with parathione, a cholinesterase inhibitor, the blood plasma levels of pseudocholinesterase and LDL were markedly decreased and HDL was increased.
The physiological role of pseudocholinesterase has not been clearly established but in Kutty, K. M., "Review: Biological Function of Cholinesterase", Clinical Biochemistry, Vol. 13 (1980), pp. 239-243, evidence is presented that the enzyme is involved with lipid metabolism.
Several types of organophosphorus compounds are known to have cholinesterase inhibiting characteristics. Although they would likely be effective at lowering blood plasma levels of pseudocholinesterase, they are highly toxic because they also inhibit acetylcholinesterase, an enzyme involved in neuro transmission.
Certain acylphosphorotriamides are known, and it has been disclosed that some of these compounds have activity as inhibitors of the enzyme urease and therefore are useful in the treatment of certain urinary tract infections. U.S. Pat. Nos. 4,182,881 issued to Bayless & Millner on Jan. 8, 1980, and 4,221,730 issued to Alaimo, Storrin & Millner on Sept. 9, 1980, disclose certain acylphosphorotriamides and methods of synthesizing them and are hereby incorporated by reference.